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We thank Dr. De Caterina and colleagues for their interest in our study, which demonstrates a high diagnostic performance of a noninvasive method for computing fractional flow reserve (FFR) from coronary computed tomography angiograms (FFRCT) (1). FFRCT is calculated by computational simulation of adenosine-mediated hyperemia rather than by actual administration of adenosine. This allows FFRCT to determine coronary flow and pressure without additional medications or image acquisition. Calculation of FFRCT is enabled by a predictable response of adenosine to reduce microcirculatory resistance downstream of epicardial coronary arteries. As discussed in our paper, the microcirculation reacts predictably to maximal hyperemia in patients with normal coronary flow, which reflects the fact that the maximal potential change in peripheral resistance from baseline to hyperemic conditions is preserved for microcirculatory vascular beds. In patients without coronary artery disease, the change in epicardial resistance is small between rest and hyperemia and allows the establishment of the limits of maximal change in microcirculatory resistance achievable in patients with microcirculatory dysfunction. Notably, this concept underscores the very definition of FFR, which also assumes that hyperemic microcirculatory resistance distal to a stenosis is identical to the resistance in the hypothetical case that the coronary arteries have no stenosis.

We agree with Dr. De Caterina and colleagues that coronary flow reserve (CFR) demonstrates variability for different patients. CFR is a different metric from FFR, given its dependence on all factors that affect blood supply to the microcirculation, including aortic pressure, epicardial resistance, and microcirculatory resistance. In this regard, CFR may be abnormal even as the response of the microcirculation to adenosine remains normal.

We agree that FFR is influenced by “the amount of viable myocardium subtended by the epicardial coronary branch harboring the stenosis.” This input condition is meticulously factored into all FFRCT models by setting the resistance of a coronary artery distal to a stenosis to be inversely (but not linearly) related to the size of the distal vessel. As blood vessels adapt proportionally to flow, a vessel feeding a dysfunctional territory will decrease in caliber and result in increased resistance in FFRCT models. This adaptive process is time dependent, and, thus, patients with recent myocardial infarctions were excluded from our study.

We disagree with the claim of Dr. De Caterina and colleagues that the utility of FFR is limited to lesions of intermediate stenosis. Angiographic stenosis is a highly unreliable surrogate for ischemia, in which a significant proportion of anatomically high-grade lesions do not cause ischemia. Application of FFRCT to these lesions may be invaluable for avoiding unnecessary invasive procedures provoked by physiologically irrelevant lesions. Conversely, even for anatomically mild lesions, a non-negligible rate of ischemia is consistently noted. Application of FFRCT to these lesions may identify patients whose lesions fall below an anatomic threshold of “severe” but who experience ischemic symptoms. In this regard, FFRCT should be considered an invaluable adjunct to coronary computed tomography angiography for lesions in all stenosis categories.

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